The duration of action of orally administered drugs in tablets or capsules is often extended by utilizing a controlled release method of delivery wherein an active pharmaceutical agent is coated and/or encapsulated and/or otherwise entrapped by a material that delays dissolution of the active agent. This method of delivery requires a larger amount of active agent than immediate release formulations to allow for a longer duration of action. Intentional or unintentional mechanical processing of such controlled release tablets or capsule beads could compromise the controlled release action of such formulations, and thereby may produce, subsequent to administration, toxic levels of active drug. Thus, for example, controlled release morphine marketed under the name Avinza® and controlled release oxycodone marketed under the name OxyContin® contain sufficient opioid to produce powerful euphoria as well as potentially fatal respiratory depression when controlled release tablets or capsule beads are chewed, crushed, ground, or otherwise broken so as to compromise the controlled release action of the formulation as indicated by the black box warning on the package insert for OxyContin® and Avinza®).
Because one can easily achieve a powerful morphine-like high after oral intravenous or nasal administration of crushed tablets or capsule beads, the abuse potential of these formulations is great. Consequently, abuse of OxyContin® has become a serious problem as evidenced by medical examiner reports that attribute several hundred deaths per year to abuse of sustained release oxycodone, and as evidenced by the substantial fraction of new enrollees in methadone treatment centers who indicate sustained release oxycodone as their primary drug of abuse.
Numerous U.S. Publications (e.g. U.S. Pat. Nos. 6,475,494; 6,451,806; 6,375,957; 6,277,384; 6,228,863; 4,785,000; 4,769,372; 4,661,492; 4,457,933; and 3,966,940) describe the addition of an opioid antagonist such as naloxone or naltrexone to formulations of opioid agonists for purposes of lowering their abuse potential. Typically this approach relies on the use of a form and/or amount of antagonist that is able to neutralize the opioid agonist when the contents of crushed tablets are administered parenterally, but not when unbroken tablets are administered orally as medically indicated. An oral formulation of the opioid pentazocine marketed under the name TALWIN® Nx contains naloxone to impede abusive intravenous administration. Abusive intravenous administration of TALWIN Nx, however, may cause harmful withdrawal syndromes in narcotic dependent individuals. Although Talwin Nx has a lower potential for abusive parenteral administration than previously marketed oral pentazocine formulations containing no antagonist, it still is subject to abusive oral administration. U.S. Pat. Nos. 5,149,538 and 5,236,714 discuss the use of antagonists to impede abuse of opiod formulations that are medically indicated for transdermal administration. U.S. Pat. Nos. 4,457,933 and 6,475,494 disclose that the presence of an appropriate amount of an opioid antagonist in an agonist formulation medically indicated for oral administration may also reduce abusive oral administration of that formulation. This reduction has been attributed (U.S. Pat. No. 6,475,494) to an aversive effect of the antagonist in physically dependent individuals. WO 02094254 describes addition of an appropriate amount of capsaicin to an oral formulation to deter abusers from crushing prescription pharmaceutical tablets for abusive snorting, injection or ingestion.
Other side effects of opioid analgesics include gastrointestinal dysfunction caused by the opioids binding to the μ receptors present in the gastrointestinal tract. The side-effects in the stomach include a reduction in the secretion of hydrochloric acid, decreased gastric motility, thus prolonging gastric emptying time, which can result in esophageal reflux. Passage of the gastric contents through the duodenum may be delayed by as much as 12 hours, and the absorption of orally administered drugs is retarded. In the small intestines the opioid analgesics diminish biliary, pancreatic and intestinal secretions and delay digestion of food in the small intestine. Resting tone is increased and periodic spasms are observed. The amplitude of the nonpropulsive type of rhythmic, segmental contractions is enhanced, but propulsive contractions are markedly decreased. Water is absorbed more completely because of the delayed passage of bowel contents, and intestinal secretion is decreased increasing the viscosity of the bowel contents. Propulsive peristaltic waves in the colon are diminished or abolished after administration of opioids, and tone is increased to the point of spasm. The resulting delay in the passage of bowel contents causes considerable desiccation of the feces, which, in turn retards their advance through the colon. The amplitude of the non-propulsive type of rhythmic contractions of the colon usually is enhanced. The tone of the anal sphincter is greatly augmented, and reflex relaxation in response to rectal distension is reduced. These actions, combined with inattention to the normal sensory stimuli for defecation reflex due to the central actions of the drug, contribute to opioid-induced constipation.
Although addition of opioid antagonists and other aversive agents to pharmaceutical tablets or capsules may well prevent abuse, they may also do harm. Thus, there is a need for the developments of a new class of opioid analgesics that are abuse resistant and have lower propensity to agonize the μ receptors in the gastrointestinal tract than the opioid analgesics present in the prior art.